Appendix 5. Expanded Discussion of What’s New in the Guideline.....2932

Preamble and Transition to ACC/AHA Guidelines to Reduce Cardiovascular Risk

The goals of the American College of Cardiology (ACC) and the American Heart Association (AHA) are to prevent cardiovascular diseases; improve the management of people who have these diseases through professional education and research; and develop guidelines, standards, and policies that promote optimal patient care and cardiovascular health. Toward these objectives, the ACC and AHA have collaborated with the National Heart, Lung, and Blood Institute (NHLBI) and stakeholder and professional organizations to develop clinical practice guidelines for assessment of cardiovascular risk, lifestyle modifications to reduce cardiovascular risk, management of blood cholesterol in adults, and management of overweight and obesity in adults.

In 2008, the NHLBI initiated these guidelines by sponsoring rigorous systematic evidence reviews for each topic by expert panels convened to develop critical questions (CQs), interpret the evidence, and craft recommendations. In response to the 2011 report from the Institute of Medicine on the development of trustworthy clinical guidelines (1), the NHLBI Advisory Council recommended that the NHLBI focus specifically on reviewing the highest-quality evidence and partner with other organizations to develop recommendations (2,3). Accordingly, in June 2013 the NHLBI initiated collaboration with the ACC and AHA to work with other organizations to complete and publish the 4 guidelines noted above and make them available to the widest possible constituency. Recognizing that the Expert Panels/Work Groups did not consider evidence beyond 2011 (except as specified in the methodology), the ACC, AHA, and collaborating societies plan to begin updating these guidelines starting in 2014.

The joint ACC/AHA Task Force on Practice Guidelines (Task Force) appointed a subcommittee to shepherd this transition, communicate the rationale and expectations to the writing panels and partnering organizations, and expeditiously publish the documents. The ACC/AHA and partner organizations recruited a limited number of expert reviewers for fiduciary examination of content, recognizing that each document had undergone extensive peer review by representatives of the NHLBI Advisory Council, key federal agencies, and scientific experts. Each writing panel responded to comments from these reviewers. Clarifications were incorporated where appropriate, but there were no substantive changes because the bulk of the content was undisputed.

Although the Task Force led the final development of these prevention guidelines, they differ from other ACC/AHA guidelines. First, as opposed to an extensive compendium of clinical information, these documents are significantly more limited in scope and focus on selected CQs on each topic, based on the highest-quality evidence available. Recommendations were derived from randomized trials, meta-analyses, and observational studies evaluated for quality and were not formulated when sufficient evidence was not available. Second, the text accompanying each recommendation is succinct, summarizing the evidence for each question. The Full Panel/Work Group Reports include more detailed information about the evidence statements that serve as the basis for recommendations. Third, the format of the recommendations differs from other ACC/AHA guidelines. Each recommendation has been mapped from the NHLBI grading format to the ACC/AHA Classification of Recommendation/Level of Evidence (COR/LOE) construct (Table 1) and is expressed in both formats. Because of the inherent differences in grading systems and the clinical questions driving the recommendations, alignment between the NHLBI and ACC/AHA formats is in some cases imperfect. Explanations of these variations are noted in the recommendation tables, where applicable.

In consultation with NHLBI, the policies adopted by the writing panels to manage relationships of authors with industry and other entities (RWI) are outlined in the methods section of each panel report. These policies were in effect when this effort began in 2008 and throughout the writing process and voting on recommendations, until the process was transferred to ACC/AHA in 2013. In the interest of transparency, the ACC/AHA requested that panel authors resubmit RWI disclosures as of July 2013. Relationships relevant to this guideline are disclosed in Appendix 1. None of the ACC/AHA expert reviewers had relevant RWI (Appendix 2). See Appendix 3 for a list of abbreviations used in the guideline.

Systematic evidence reports and accompanying summary tables were developed by the expert panels and NHLBI. The guideline was reviewed by the ACC/AHA Task Force and approved by the ACC Board of Trustees, and the AHA Science Advisory and Coordinating Committee. In addition, ACC/AHA sought endorsement from other stakeholders, including professional organizations. It is the hope of the writing panels, stakeholders, professional organizations, NHLBI, and Task Force that the guidelines will garner the widest possible readership for the benefit of patients, providers, and the public health.

These guidelines are meant to define practices that meet the needs of patients in most circumstances and are not a replacement for clinical judgment. The ultimate decision about care of a particular patient must be made by the healthcare provider and patient in light of the circumstances presented by that patient. As a result, situations might arise in which deviations from these guidelines may be appropriate. These considerations notwithstanding, in caring for most patients, clinicians can employ the recommendations confidently to reduce the risks of atherosclerotic cardiovascular disease (ASCVD) events.

See Tables 1a and 1b for an explanation of the NHLBI recommendation grading methodology.

1 Introduction

1.1 Organization of the Panel

The Blood Cholesterol Expert Panel (Expert Panel) was originally convened as the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel IV) appointed by the NHLBI. The Expert Panel was composed of 13 members and 3 ex-officio members, which included primary care physicians, cardiologists, endocrinologists, and experts in clinical lipidology, clinical trials, cardiovascular epidemiology and nutrition, and guideline development. The Expert Panel chair asked all panel members to disclose any conflict-of-interest information to the full panel in advance of the deliberations; members with conflicts were asked to recuse themselves from voting on any aspect of the guideline for which a conflict might exist. All 16 members of the NHLBI Adult Treatment Panel IV Panel transitioned to the ACC/AHA guideline Expert Panel. Independent contractors performed the systematic review with the assistance of the Expert Panel and provided methodological guidance to the Expert Panel.

1.2 Document Review and Approval

A formal peer review process was initially completed under the auspices of the NHLBI and included 23 expert reviewers and representatives of federal agencies. This document was also reviewed by 4 expert reviewers nominated by the ACC and the AHA when the management of the guideline transitioned to the ACC/AHA. The ACC and AHA reviewers’ RWI information is published in this document (Appendix 2).

This document was approved for publication by the governing bodies of the ACC and AHA and endorsed by the American Academy of Physician Assistants, American Association of Cardiovascular and Pulmonary Rehabilitation, American Pharmacists Association, American Society for Preventive Cardiology, Association of Black Cardiologists, Preventive Cardiovascular Nurses Association, and WomenHeart: The National Coalition for Women with Heart Disease.

1.3 Scope of Guideline

This guideline is based on the Full Panel Report, which is provided as an online-only data supplement to the guideline. The Full Panel Report contains background and additional material related to content, methodology, evidence synthesis, rationale, and references and is supported by the NHLBI Systematic Evidence Review, which can be found at http://www.nhlbi.nih.gov/guidelines/cholesterol/ser/. Table 2 provides an overview to facilitate understanding what is new in the present guideline.

The Expert Panel was charged with using data from randomized controlled trials (RCTs) and systematic reviews and meta-analyses of RCTs to update the clinical practice recommendations for the treatment of blood cholesterol levels to reduce ASCVD risk. For this guideline, ASCVD includes coronary heart disease (CHD), stroke, and peripheral arterial disease, all of presumed atherosclerotic origin. These recommendations are intended to provide a strong, evidence-based foundation for the treatment of cholesterol for the primary and secondary prevention of ASCVD in women and men.

Because RCT data were used to identify those most likely to benefit from cholesterol-lowering statin therapy, the recommendations will be of value to primary care clinicians as well as specialists concerned with ASCVD prevention. Importantly, the recommendations were designed to be easy to use in the clinical setting, facilitating the implementation of a strategy of risk assessment and treatment focused on the prevention of ASCVD. The present guideline is intended to address treatment of adults (≥21 years of age) to complement the NHLBI cardiovascular health risk-reduction guideline for children and adolescents (4).

The members of the Expert Panel acknowledge the important contributions arising from decades of genetic and biochemical studies, observational epidemiological and ecological studies, and in vitro and animal experiments that associated higher low-density lipoprotein cholesterol (LDL-C) levels with greater ASCVD risk. These studies provided the rationale for RCTs, which in turn demonstrated that lowering cholesterol levels reduced ASCVD events and thereby established a central, causal role of atherogenic cholesterol-containing lipoprotein particles, particularly LDL, in the genesis of CHD and ASCVD.

Other strategies for using drug therapy to reduce ASCVD events have been advocated, including treat-to-cholesterol target, lowest-is-best, and risk-based treatment approaches. However, only 1 approach has been evaluated in multiple RCTs—the use of fixed doses of cholesterol-lowering drugs to reduce ASCVD risk. Because the overwhelming body of evidence came from statin RCTs, the Expert Panel appropriately focused on these statin RCTs to develop evidence-based guidelines for the reduction of ASCVD risk. We recognize that this represents a significant departure from current strategies. This should not come as a surprise to clinicians. The recent guideline on heart failure has changed long-standing paradigms on the basis of the evidence, and this guideline does as well (5). Future RCTs will be needed to determine the optimal treatment strategy to provide the greatest reduction in ASCVD events with best margin of safety.

The Expert Panel acknowledges that our process did not provide for a comprehensive approach to the detection, evaluation, and treatment of lipid disorders as was done in the prior Adult Treatment Panel III Report (6). However, the present guideline was never intended to be a comprehensive approach to lipid management for purposes other than ASCVD risk reduction. A limited number of expert opinion recommendations were made only when RCT evidence was not present and after a thorough consideration of what the Expert Panel had learned from the RCTs. For the many questions about complex lipid disorders that are beyond the scope of our systematic evidence review, or for which little or no RCT data are available, it is anticipated that clinicians with lipid expertise can contribute to their management.

1.4 Methodology and Evidence Review

Although the Expert Panel was convened before the Institute of Medicine reports on practice guidelines, our evidence-based process followed most of the standards from the Institute of Medicine report, “Clinical Practice Guidelines We Can Trust” (1). The systematic review was limited to RCTs with ASCVD outcomes and systematic reviews and meta-analyses of RCTs with ASCVD outcomes. Observational studies and those with <18 months (CQ1 and CQ2) or <12 months (CQ3) of follow-up were excluded. Support was provided by a methodology contractor and a systematic review and general support contractor and included the following steps:

• An independent contractor developed a literature search strategy, based on inclusion/exclusion criteria, for each CQ.

• An independent contractor executed a systematic electronic search of the published literature from relevant bibliographic databases for each CQ. The date range for the overall literature search was January 1, 1995, through December 1, 2009. However, RCTs with hard ASCVD outcomes of myocardial infarction (MI), stroke, and cardiovascular death published after that date range were eligible for consideration until the Expert Panel began deliberations on relevant recommendations.

• RCTs that met the inclusion criteria and were independently graded as fair or good quality were included in the evidence tables for the consideration of the Expert Panel. RCTs that were graded as poor quality were excluded.

• With the assistance of independent methodologists, this evidence base was used to develop a series of evidence statements graded on the level of the evidence (high, medium, or low).

• The final evidence statements and treatment recommendations were approved by at least a majority of voting members of the Expert Panel.

• Guideline implementability appraisals, planned and coordinated by the NHLBI Implementation Work Group, were performed to identify and address barriers to guideline implementation.

In addition, the Expert Panel was able to include major RCTs and meta-analyses of RCTs published through July 2013 in our discussion and as part of the process of determining ACC/AHA grading of the NHLBI expert-level recommendations.

2 Overview of the Guideline

The RCTs identified in the systematic evidence review indicated a consistent reduction in ASCVD events from 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (statin) therapy in secondary- and primary-prevention populations, with the exception of no ASCVD event reduction when statin therapy was initiated in those with New York Heart Association class II to IV heart failure or those receiving maintenance hemodialysis. The RCTs either compared fixed doses of statins with placebo or untreated controls, or compared fixed doses of higher-intensity statins with moderate-intensity statins. These trials were not designed to evaluate the effect of titrated (dose-adjusted) statin treatment to achieve prespecified LDL-C or non–HDL-C goals.

Therefore, the Expert Panel was unable to find RCT evidence to support titrating cholesterol-lowering drug therapy to achieve target LDL-C or non–HDL-C levels, as recommended by Adult Treatment Panel III (6–8). Notably, the Expert Panel did find RCT evidence that use of therapy (e.g., niacin) to additionally lower non–HDL-C, once an LDL-C target was achieved, did not further reduce ASCVD outcomes (9). The Expert Panel also found extensive RCT evidence that the appropriate intensity of statin therapy should be used to reduce ASCVD risk in those most likely to benefit. The work of the Expert Panel was informed by the reports of the Lifestyle Management (10) and Risk Assessment Work Groups (11) (Figure 1). A summary of the major recommendations for the treatment of cholesterol to reduce ASCVD risk is provided in Table 3.

Summary of Key Recommendations for the Treatment of Blood Cholesterol to Reduce ASCVD Risk in Adults (See Tables 4, 8, 9, and 10 for the complete recommendations; and Table 5 for definition of statin intensity)

2.1 Lifestyle as the Foundation for ASCVD Risk-Reduction Efforts

It must be emphasized that lifestyle modification (i.e., adhering to a heart-healthy diet, regular exercise habits, avoidance of tobacco products, and maintenance of a healthy weight) remains a crucial component of health promotion and ASCVD risk reduction, both prior to and in concert with the use of cholesterol-lowering drug therapies. Healthy diet or lifestyle modifications were recommended as background therapy for the RCTs of cholesterol-lowering drug therapy. See the “2013 AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk” (10) for lifestyle recommendations for healthy adults. Drug therapy for lifestyle-related risk factors such as hypertension is often needed and smoking should be avoided.

2.2 Initiation of Statin Therapy

The Expert Panel found extensive and consistent evidence supporting the use of statins for the prevention of ASCVD in many higher-risk primary- and all secondary-prevention individuals without New York Heart Association class II–IV heart failure who were not receiving hemodialysis. In the RCTs reviewed, initiation of moderate-intensity therapy (lowering LDL-C by approximately 30% to <50%) or high-intensity statin therapy (lowering LDL-C by approximately ≥50%) is a critical factor in reducing ASCVD events. Moreover, statin therapy reduces ASCVD events across the spectrum of baseline LDL-C levels ≥70 mg/dL. In addition, the relative reduction in ASCVD risk is consistent for primary and secondary prevention and for various patient subgroups. Of note, the absolute reduction in ASCVD events is proportional to baseline absolute ASCVD risk. Therefore, statin therapy is recommended for individuals at increased ASCVD risk who are most likely to experience a net benefit in terms of the potential for ASCVD risk reduction and the potential for adverse effects (Table 3; Figure 2).

Summary of Statin Initiation Recommendations for the Treatment of Blood Cholesterol to Reduce ASCVD Risk in Adults (See Figures 3, 4, and 5 for More Detailed Management Information)

Colors correspond to the Classes of Recommendation in Table 1. Assessment of the potential for benefit and risk from statin therapy for ASCVD prevention provides the framework for clinical decision making incorporating patient preferences.

*Percent reduction in LDL-C can be used as an indication of response and adherence to therapy, but is not in itself a treatment goal.

†The Pooled Cohort Equations can be used to estimate 10-year ASCVD risk in individuals with and without diabetes. The estimator within this application should be used to inform decision making in primary prevention patients not on a statin.

‡Consider moderate-intensity statin as more appropriate in low-risk individuals.

§For those in whom a risk assessment is uncertain, consider factors such as primary LDL-C ≥160 mg/dL or other evidence of genetic hyperlipidemias, family history of premature ASCVD with onset <55 years of age in a first-degree male relative or <65 years of age in a first-degree female relative, hs-CRP ≥2 mg/L, CAC score ≥300 Agatston units, or ≥75th percentile for age, sex, and ethnicity (for additional information, see http://www.mesa-nhlbi.org/CACReference.aspx), ABI <0.9, or lifetime risk of ASCVD. Additional factors that may aid in individual risk assessment may be identified in the future.

‖Potential ASCVD risk-reduction benefits. The absolute reduction in ASCVD events from moderate- or high-intensity statin therapy can be approximated by multiplying the estimated 10-year ASCVD risk by the anticipated relative-risk reduction from the intensity of statin initiated (∼30% for moderate-intensity statin or ∼45% for high-intensity statin therapy). The net ASCVD risk-reduction benefit is estimated from the number of potential ASCVD events prevented with a statin, compared to the number of potential excess adverse effects.

¶Potential adverse effects. The excess risk of diabetes is the main consideration in ∼0.1 excess cases per 100 individuals treated with a moderate-intensity statin for 1 year and ∼0.3 excess cases per 100 individuals treated with a high-intensity statin for 1 year. In RCTs, both statin-treated and placebo-treated participants experienced the same rate of muscle symptoms. The actual rate of statin-related muscle symptoms in the clinical population is unclear. Muscle symptoms attributed to statin therapy should be evaluated (see Table 8, Safety Recommendation 8).

On the basis of this large and consistent body of evidence, 4 major statin benefit groups were identified for whom the ASCVD risk reduction clearly outweighs the risk of adverse events based on a strong body of evidence. These are 1) secondary prevention in individuals with clinical ASCVD, 2) primary prevention in individuals with primary elevations of LDL-C ≥190 mg/dL, 3) primary prevention in individuals with diabetes 40 to 75 years of age who have LDL-C 70 to 189 mg/dL, and 4) primary prevention in individuals without diabetes and with estimated 10-year ASCVD risk ≥7.5%, 40 to 75 years of age who have LDL-C 70 to 189 mg/dL. Moderate evidence supports the use of statins for primary prevention in individuals with 5% to <7.5% 10-year ASCVD risk, 40 to 75 years of age with LDL-C 70 to 189 mg/dL. Selected individuals with <5% 10-year ASCVD risk, or <40 or >75 years of age may also benefit from statin therapy. Clinicians and patients should engage in a discussion of the potential for ASCVD risk-reduction benefits, adverse effects, drug–drug interactions, and consider patient preferences for treatment. This discussion also provides the opportunity to re-emphasize healthy-lifestyle habits and address other risk factors.

Clinical ASCVD is defined by the inclusion criteria for the secondary-prevention statin RCTs (acute coronary syndromes, a history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease presumed to be of atherosclerotic origin). For primary prevention in individuals without clinical ASCVD or diabetes who have an LDL-C 70 to 189 mg/dL, the estimated absolute 10-year risk of ASCVD (defined as nonfatal MI, CHD death, or nonfatal and fatal stroke) should be used to guide the initiation of statin therapy. The 10-year ASCVD risk should be estimated with the Pooled Cohort Equations (Section 4.7). For the primary prevention of ASCVD in individuals with diabetes (diabetes mellitus type 1 and type 2), estimated 10-year ASCVD risk can also be used to guide the intensity of statin therapy. For those with clinical ASCVD or with LDL-C ≥190 mg/dL who are already in a statin benefit group, it is not appropriate to estimate 10-year ASCVD risk. In primary prevention, additional factors may influence ASCVD risk in those for whom a risk-based decision is unclear. These include a primary LDL-C ≥160 mg/dL or other evidence of genetic hyperlipidemias, family history of premature ASCVD with onset <55 years of age in a first-degree male relative or <65 years of age in a first-degree female relative, high-sensitivity C-reactive protein ≥2 mg/L, coronary artery calcium score ≥300 Agatston units or ≥75th percentile for age, sex, and ethnicity (for additional information, see http://www.mesa-nhlbi.org/CACReference.aspx.), ankle-brachial index <0.9, and elevated lifetime risk of ASCVD.

The findings support the use of statins to prevent both nonfatal and fatal ASCVD events. Such an approach can reduce the large burden of disability from nonfatal stroke (for which women are at higher risk than men) and nonfatal CHD events. Primary and secondary prevention of ASCVD with statins can positively impact rising healthcare costs. In addition, a high level of evidence was found that statins reduce total mortality in individuals with a history of prior ASCVD events (e.g., secondary-prevention settings). In individuals with no prior history of ASCVD events (e.g., primary-prevention settings), there is moderate evidence that statins reduce total mortality in individuals at increased ASCVD risk. It should be noted that 2 meta-analyses published after the completion of the Expert Panel’s systematic review provide strong evidence that statins reduce total mortality in primary prevention (12,13).

3 Critical Questions and Conclusions

3.1 Identification of CQs

Although limited to 3 CQs, these questions were considered the most important to answer in order to identify whom to treat and with what treatment(s) and to consider how intensively the treatments should be used. The first 2 CQs evaluated the evidence for LDL-C and non–HDL-C goals for the secondary and primary prevention of ASCVD with cholesterol-lowering drug therapy. Titration to specific LDL-C goals has been considered a fundamental therapeutic strategy in deciding on the adequacy of cholesterol-lowering therapy for secondary and primary prevention. Therefore, a comprehensive systematic review of the evidence base supporting this concept was essential. The third CQ had several objectives:

• Identify groups of patients who will benefit from pharmacological treatment,

• Define the pharmacological treatment(s) for which there is the best evidence of net benefit, and

3.1.1 CQ1: LDL-C and Non–HDL-C Goals in Secondary Prevention

CQ1: What is the evidence for LDL-C and non–HDL-C goals for the secondary prevention of ASCVD?

The Expert Panel reviewed 19 RCTs to answer CQ1. Although CQ1 is supported conceptually by an extrapolation of observational studies and observational data from RCTs, no data were identified for treatment or titration to a specific LDL-C goal in adults with clinical ASCVD. The majority of studies confirming the efficacy of cholesterol reduction in improving clinical outcomes in patients with clinical ASCVD used a single fixed-dose statin to lower LDL-C levels. In the 4S trial, 37% had the dose of simvastatin raised from 20 mg/d to 40 mg/d to achieve a total cholesterol level <200 mg/dL (16). The Expert Panel was unable to find any RCTs that evaluated titration of all individuals in a treatment group to specific LDL-C targets <100 mg/dL or <70 mg/dL, nor were any RCTs comparing 2 LDL-C treatment targets identified. No statin RCTs reporting on-treatment non–HDL-C levels were identified. (In CQ3, statin-nonstatin combination therapy was evaluated.)

3.1.2 CQ2: LDL-C and Non–HDL-C Goals in Primary Prevention

CQ2: What is the evidence for LDL-C and non–HDL-C goals for the primary prevention of ASCVD?

The Expert Panel reviewed 6 RCTs. The 4 studies confirming the efficacy of cholesterol reduction in improving clinical outcomes in patients without ASCVD used fixed-dose statin therapy to lower LDL-C levels. In the AFCAPS-TEXCAPS (Air Force/Texas Coronary Atherosclerosis Prevention Study) trial (17), in 50% of participants, the lovastatin dose was raised from 20 mg to 40 mg to achieve an LDL-C level <110 mg/dL. In the MEGA (Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese) trial (18), the dose of pravastatin could be uptitrated from 10 mg to 20 mg to achieve a total cholesterol level <220 mg/dL. The Expert Panel did not find any RCTs that evaluated titration of all individuals in a treatment group to specific LDL-C targets <100 mg/dL or <70 mg/dL, nor were any RCTs comparing 2 LDL-C treatment targets identified. No trials reported on-treatment non–HDL-C levels.

3.1.3 CQ3: Efficacy and Safety of Cholesterol-Lowering Medications

CQ3: For primary and secondary prevention, what is the impact on lipid levels, effectiveness, and safety of specific cholesterol-modifying drugs used for lipid management in general and in selected subgroups?

The populations examined included primary-prevention adult patients who could not have a diagnosis of CHD or cardiovascular disease. Interventions included pharmacotherapy with single-drug therapies or combination-drug therapies with any drug therapy used for treating blood cholesterol, including statins, fibrates (fenofibrate, gemfibrozil), nicotinic acid (niacin in immediate-, slow-, or extended-release form), bile acid sequestrants, ezetimibe, omega-3 fatty acids (also called marine fatty acids, including eicosapentaenoic acid alone, docosahexanoic acid alone, eicosapentaenoic acid plus docosahexanoic acid, and alpha-linolenic acid). There were no ASCVD outcomes identified for plant sterols, sterol esters, stanols, or stanol esters. A single ASCVD outcomes trial (19) used Xuezhikang, an extract from red yeast Chinese rice, which was not available in the United States during the timeframe for evidence review, so no recommendations were made regarding its use.

The recommendations synthesize the evidence retrieved for answering CQ3, along with the evidence from the trials included in CQ1 and CQ2, to guide the use of cholesterol-lowering drugs for secondary or primary prevention of ASCVD.

4 Statin Treatment: Recommendations

For each recommendation, the grades of the recommendation by both the NHLBI and ACC/AHA methods are provided. Major treatment recommendations are listed in Table 4, and statin intensities are defined in Table 5. The safety (statin and nonstatin) recommendations are in Section 5. A complete listing of the evidence statements supporting each recommendation, along with the references, is provided in Appendix 4.

High-, Moderate-, and Low-Intensity Statin Therapy (Used in the RCTs Reviewed by the Expert Panel)∗

4.1 Intensity of Statin Therapy in Primary and Secondary Prevention

The Expert Panel defines the intensity of statin therapy on the basis of the average expected LDL-C response to a specific statin and dose. “High-intensity,” “moderate-intensity,” and “low-intensity” statin therapy definitions were derived from the systematic reviews for CQ1 and CQ2. The basis for differentiation among specific statins and doses arose from the RCTs included in CQ1, where there was a high level of evidence that high-intensity statin therapy with atorvastatin 40 mg to 80 mg reduced ASCVD risk more than moderate-intensity statin therapy with atorvastatin 10 mg, pravastatin 40 mg, or simvastatin 20 mg to 40 mg twice daily. Classifying specific statins and doses by the percent reduction in LDL-C level is based on evidence that the relative reduction in ASCVD risk from statin therapy is related to the degree by which LDL-C is lowered. However, no variation in the relative reduction in ASCVD risk was observed after the data were adjusted for LDL-C reduction. Furthermore, there is no differentiation between the specific statins and doses used in primary- and secondary-prevention RCTs, according to a high level of evidence that statins reduce ASCVD risk similarly in both populations.

Percent reductions in LDL-C for a specific statin and dose were calculated for the RCTs included in individual meta-analyses conducted by the Cholesterol Treatment Trialists (CTT) in 2010 (20), in which statin therapy reduced ASCVD events. High-intensity statin therapy on average lowers LDL-C by approximately ≥50%, moderate-intensity statin therapy lowers LDL-C by approximately 30% to <50%, and lower-intensity statin therapy lowers LDL-C by <30% (Table 5).

4.2 LDL-C and Non–HDL-C Treatment Goals

The Expert Panel did not find evidence to support titrating cholesterol-lowering drug therapy to achieve optimal LDL-C or non–HDL-C levels because the clinical trials were essentially fixed-dose trials (CQ1 and CQ2). Dosage increases did occur in a few RCTs with the intent of maximizing statin therapy. Therefore, these were not truly tests of defining optimal goals for LDL-C in primary and secondary prevention because not all individuals in the statin treatment groups received drug therapy titrated to achieve a specific LDL-C or non–HDL-C goal, nor were specific treatment targets compared. One RCT in CQ3 was identified that showed no additional ASCVD event reduction from the addition of nonstatin therapy to further lower non–HDL-C levels once an LDL-C goal had been reached. In AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes), the additional reduction in non–HDL-C levels (as well as further reductions in apolipoprotein B, lipoprotein[a], and triglycerides in addition to HDL-C increases) with niacin therapy did not further reduce ASCVD risk in individuals treated to LDL-C levels of 40 to 80 mg/dL (9).

Therefore, given the absence of data on titration of drug therapy to specific goals, no recommendations are made for or against specific LDL-C or non–HDL-C goals for the primary or secondary prevention of ASCVD.

4.3 Secondary Prevention

Women and men with clinical ASCVD (defined from the RCT inclusion criteria as acute coronary syndromes; history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease presumed to be of atherosclerotic origin) arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease presumed to be of atherosclerotic origin are at increased risk for recurrent ASCVD and ASCVD death. An extensive body of evidence demonstrates that high-intensity statin therapy reduces ASCVD events more than moderate-intensity statin therapy (Table 4) in individuals with clinical ASCVD.

High-intensity statin therapy should be initiated for adults ≤75 years of age with clinical ASCVD who are not receiving statin therapy, or the intensity should be increased in those receiving a low- or moderate-intensity statin, unless they have a history of intolerance to high-intensity statin therapy or other characteristics that could influence safety (Section 5). This is consistent with RCT data. In 2 trials, patients were previously treated with a moderately intensive statin (46,47), and in 2 trials, 75% to 97% of patients had not received prior statin therapy (48,78). The high-intensity statins atorvastatin 80 mg and rosuvastatin 20 mg daily reduce LDL-C ≥50% on average and have been shown to reduce ASCVD events in RCTs.

Although atorvastatin 40 mg reduces LDL-C by approximately ≥50%, this dose was used in only 1 RCT if the participant was unable to tolerate atorvastatin 80 mg/dL. Whether an individual receiving atorvastatin 40 mg should be uptitrated to atorvastatin 80 mg should be based on the potential for an ASCVD risk-reduction benefit and the potential for adverse effects, drug–drug interactions, and consider patient preferences.

In individuals with clinical ASCVD in whom high-intensity statin therapy would otherwise be used, either when high-intensity statin therapy is contraindicated or when characteristics predisposing to statin-associated adverse effects are present, moderate-intensity statin should be used as the second option, if tolerated (Section 5). In the relatively few individuals >75 years of age who were included in RCTs of high- versus moderate-intensity statin therapy, there was no clear evidence of an additional reduction in ASCVD events from high-intensity statin therapy. In contrast, individuals >75 years of age did experience a reduction in ASCVD events in the trials of mostly moderate-intensity statin therapy, as compared with control. Therefore, moderate-intensity statin therapy should be considered for individuals >75 years of age with clinical ASCVD. However, in acknowledgment that older participants in RCTs were likely to be healthier than many older individuals in the general population, the use of statin therapy should be individualized in persons >75 years of age with clinical ASCVD, according to the potential for ASCVD risk-reduction benefits, adverse effects, drug–drug interactions, and consider patient preferences. The Expert Panel considers it reasonable to continue statin therapy in persons >75 years of age who have clinical ASCVD and are tolerating statin therapy.

The flow diagram for the initiation and management of statin therapy in individuals with clinical ASCVD is provided in Figure 3.

*Fasting lipid panel preferred. In a nonfasting individual, a non–HDL-C level ≥220 mg/dL could indicate genetic hypercholesterolemia that requires further evaluation or a secondary etiology. If nonfasting triglycerides are ≥500 mg/dL, a fasting lipid panel is required.

†It is reasonable to evaluate the potential for ASCVD benefits and for adverse effects, and to consider patient preferences, in initiating or continuing a moderate- or high-intensity statin in individuals with ASCVD who are >75 years of age.

4.4 Primary Prevention in Individuals ≥21 Years of Age With LDL-C ≥190 mg/dL

This guideline recognizes that individuals ≥21 years of age with primary, severe elevations of LDL-C (≥190 mg/dL) have a high lifetime risk for ASCVD events. This is due to their lifetime exposure to markedly elevated LDL-C levels arising from genetic causes. Thus, at age 21, these individuals should receive statin therapy if they have not already been diagnosed and treated before this age. Although in most clinical trials individuals with LDL-C ≥190 mg/dL were not included because of their need for treatment, extensive evidence shows that each 39-mg/dL reduction in LDL-C by statin therapy reduces ASCVD risk by about 20%. Patients with primary elevations of LDL-C ≥190 mg/dL require even more substantial reductions in their LDL-C levels and intensive management of other risk factors to reduce their ASCVD event rates. Therefore, it is reasonable to use high-intensity statin therapy to achieve at least a 50% reduction. It is recognized that maximal statin therapy might not be adequate to lower LDL-C sufficiently to reduce ASCVD event risk in individuals with primary severe elevations of LDL-C. In addition to a maximally tolerated dose of statin, nonstatin cholesterol-lowering medications are often needed to lower LDL-C to acceptable levels in these individuals. Because the hypercholesterolemia in these high-risk individuals is often genetically determined, family screening is especially important in this group to identify additional family members who would benefit from assessment and early treatment.

Secondary causes of severe elevations of LDL-C ≥190 mg/dL and triglycerides ≥500 mg/dL often contribute to the magnitude of the hyperlipidemia and should be evaluated and treated appropriately. For guidance, we note that in a lipid specialty clinic, the most frequently encountered secondary conditions were excessive alcohol intake, uncontrolled diabetes, and overt albuminuria (79). Table 6 focuses on secondary causes of hyperlipidemia most likely encountered in clinical practice (80). Management of individuals with fasting triglycerides ≥500 mg/dL has been addressed in an AHA statement (45).

*Fasting lipid panel preferred. In a nonfasting individual, a non–HDL-C level ≥220 mg/dL could indicate genetic hypercholesterolemia that requires further evaluation or a secondary etiology. If nonfasting triglycerides are ≥500 mg/dL, a fasting lipid panel is required.

†The Pooled Cohort Equations can be used to estimate 10-year ASCVD risk in individuals with and without diabetes.

‡For those in whom a risk assessment is uncertain, consider factors such as primary LDL-C ≥160 mg/dL or other evidence of genetic hyperlipidemias; family history of premature ASCVD with onset <55 years of age in a first-degree male relative or <65 years of age in a first-degree female relative, high-sensitivity C-reactive protein ≥2 mg/L; CAC ≥300 Agatston units or ≥75th percentile for age, sex, and ethnicity (for additional information, see http://www.mesa-nhlbi.org/CACReference.aspx); ABI <0.9; or lifetime risk of ASCVD. Additional factors that may aid in individual risk assessment could be identified in the future.

§1) Potential ASCVD risk-reduction benefits. The absolute reduction in ASCVD events from moderate- or high-intensity statin therapy can be approximated by multiplying the estimated 10-year ASCVD risk by the anticipated relative-risk reduction from the intensity of statin initiated (∼30% for moderate-intensity statin or ∼45% for high-intensity statin therapy). The net ASCVD risk-reduction benefit is estimated from the number of potential ASCVD events prevented with a statin, compared to the number of potential excess adverse effects. 2) Potential adverse effects. The excess risk of diabetes is the main consideration in ∼0.1 excess cases per 100 individuals treated with a moderate-intensity statin for 1 year and ∼0.3 excess cases per 100 individuals treated with a high-intensity statin for 1 year. In RCTs, both statin-treated and placebo-treated participants experienced the same rate of muscle symptoms. The actual rate of statin-related muscle symptoms in the clinical population is unclear. Muscle symptoms attributed to statin therapy should be evaluated (see Table 8, Safety Recommendation 8).

4.5 Primary Prevention in Individuals With Diabetes

A high level of evidence supports the use of moderate-intensity statin therapy in persons with diabetes who are 40 to 75 years of age. The only trial of high-intensity statin therapy in primary prevention was performed in a population without diabetes. However, a high level of evidence existed for event reduction with statin therapy in individuals with a ≥7.5% estimated 10-year ASCVD risk (Section 4.6) who did not have diabetes to recommend high-intensity statin therapy preferentially for individuals with diabetes and a ≥7.5% estimated 10-year ASCVD risk (Section 4.7). This consideration for those with diabetes who are 40 to 75 years of age recognizes that these individuals are at substantially increased lifetime risk for ASCVD events and death. Moreover, individuals with diabetes experience greater morbidity and worse survival after the onset of clinical ASCVD. In persons with diabetes who are <40 years of age or >75 years of age, or whose LDL-C is <70 mg/dL, statin therapy should be individualized on the basis of considerations of ASCVD risk-reduction benefits, the potential for adverse effects and drug–drug interactions, and patient preferences (Figure 4).

4.6 Primary Prevention in Individuals Without Diabetes and With LDL-C 70 to 189 mg/dL

In individuals 40 to 75 years of age with LDL-C 70 to 189 mg/dL who do not have clinical ASCVD or diabetes, initiation of statin therapy based on estimated 10-year ASCVD risk is recommended, regardless of sex, race, or ethnicity (Section 4.7). Point estimates of statin-associated reductions in the relative risk of ASCVD in primary prevention are similar for both women and men. There also is no evidence that the ASCVD risk-reduction benefit or adverse-effect profiles differ by race.

To better identify those individuals without ASCVD who would most benefit from statin therapy to reduce ASCVD risk, data were used from the 3 exclusively primary-prevention RCTs that included individuals with LDL-C levels <190 mg/dL, almost all of whom had LDL-C levels ≥70 mg/dL (17,18,49). From these trials, an estimate of the expected 10-year ASCVD event rates was derived from the placebo groups. The rates of excess adverse events in the statin treatment groups were obtained from meta-analyses of statin RCTs. A high level of evidence for an ASCVD risk-reduction benefit from initiation of moderate- or high-intensity statin therapy in individuals 40 to 75 years of age with ≥7.5% estimated 10-year ASCVD risk was found (Section 4.7). The reduction in ASCVD risk clearly outweighs the potential for adverse effects (Table 7). Thus, it is recommended that individuals 40 to 75 years of age, who are not already candidates for statin therapy on the basis of the presence of clinical ASCVD, diabetes, or LDL-C ≥190 mg/dL, receive statin therapy if they have a ≥7.5% estimated 10-year risk for ASCVD and LDL-C 70 to 189 mg/dL. Although only 1 exclusively primary-prevention RCT included individuals with LDL-C 70 to <100 mg/dL, the Cholesterol Treatment Trialists 2010 meta-analysis found a relative reduction in ASCVD events of similar magnitude across the spectrum of LDL-C levels ≥70 mg/dL (20). Given that the relative risk reduction is similar across the range of LDL-C 70 to 189 mg/dL, the absolute benefit of statin therapy in primary prevention is determined by the global risk estimate using all the risk factor information and is reflected in the estimated 10-year ASCVD risk.

Rationale for the Expert Panel Approach to Primary-Prevention Guidelines

A conservative estimate of adverse events includes excess cases of new-onset diabetes and rare cases of myopathy and hemorrhagic stroke. The rate of excess diabetes varies by statin intensity. For moderate-intensity statins, approximately 0.1 excess case of diabetes per 100 statin-treated individuals per year has been observed, and for high-intensity statins, approximately 0.3 excess case of diabetes per 100 statin-treated individuals per year has been observed (52,81). The long-term adverse effects of statin-associated cases of diabetes over a 10-year period are unclear and are unlikely to be equivalent to an MI, stroke, or ASCVD death. Myopathy (∼0.01 excess case per 100) and hemorrhagic stroke (∼0.01 excess case per 100) make minimal contributions to excess risk from statin therapy (13).

Although a similar level of evidence of a reduction in ASCVD events from moderate- and high-intensity statin therapy is present for those with a 5% to <7.5% estimated 10-year ASCVD risk, the potential for adverse effects may outweigh the potential for ASCVD risk-reduction benefit when high-intensity statin therapy is used in this risk group. However, for moderate-intensity statin therapy, the ASCVD risk reduction clearly exceeds the potential for adverse effects.

Before initiating statin therapy for the primary prevention of ASCVD in adults with ≥7.5% or 5% to <7.5% estimated 10-year ASCVD risk, it is reasonable for clinicians and patients to engage in a discussion of the proposed therapy. This discussion should include the potential for ASCVD benefit, the potential for adverse effects and drug–drug interactions, and consideration of patient preferences for treatment.

No primary-prevention RCT data were available for individuals 21 to 39 years of age, and few data were available for individuals >75 years of age. Additionally, in individuals 40 to 75 years of age with <5% estimated 10-year ASCVD risk, the net benefit from statin therapy over a 10-year period may be small. Therefore, in adults with LDL-C <190 mg/dL who are not otherwise identified in a statin benefit group or for whom a risk-based treatment decision is uncertain after quantitative risk assessment, clinician knowledge, experience, and skill (“the art of medicine”) and patient preferences all contribute to the decision to initiate statin therapy (82). Before initiation of statin therapy, the clinician-patient discussion should include consideration of the potential for ASCVD risk-reduction benefits, adverse effects, and drug–drug interactions. Additional factors may also be considered to inform treatment decision making in selected individuals. Factors that can contribute to assessment of ASCVD risk include primary LDL-C ≥160 mg/dL or other evidence of genetic hyperlipidemias; family history of premature ASCVD with onset <55 years of age in a first-degree male relative or <65 years of age in a first-degree female relative; high-sensitivity C-reactive protein ≥2 mg/L, coronary artery calcium score ≥300 Agatston units or ≥75th percentile for age, sex, and ethnicity (for additional information, see http://www.mesa-nhlbi.org/CACReference.aspx); ankle-brachial index <0.9; or elevated lifetime risk of ASCVD. Additional factors that might aid in individual risk assessment could be identified in the future.

For an individual <40 years of age, the 10-year horizon might not be optimal for predicting lifetime risk of ASCVD (see 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk) (11). Future RCTs will be needed to determine the optimal age at which to initiate statin therapy to reduce ASCVD risk, as well as to determine the optimum duration of statin therapy.

4.7 Risk Assessment in Primary Prevention

To estimate more closely the total burden of ASCVD, this guideline recommends a comprehensive assessment of the estimated 10-year risk for an ASCVD event that includes both CHD and stroke. This is in contrast to the use of an estimated 10-year risk for hard CHD (defined as nonfatal MI and CHD death) (83).

This guideline does not require specific risk factor counting for risk assessment or the use of RCT risk factor inclusion criteria to determine statin eligibility. Rather, a global ASCVD risk assessment to guide initiation of statin therapy was chosen for several important reasons (see rationale in Table 7 and further discussion in Section 7.3 of the Full Panel Report Supplement): 1) The Cholesterol Treatment Trialists individual-level meta-analyses were used to evaluate the effect of statins in various important patient subgroups, including risk factor cutpoints used for RCT eligibility. The Expert Panel found that statin therapy reduces ASCVD events regardless of risk factor characteristics in both primary and secondary prevention. Therefore, the rationale for using fixed cutpoints to determine whether statin therapy should be used is refuted by a consideration of the total body of evidence. 2) Use of absolute ASCVD risk facilitates a quantitative assessment of the potential for an ASCVD risk-reduction benefit as compared with the potential for adverse effects. 3) Use of an RCT eligibility criteria–based approach results in failure to identify a substantial proportion of higher-risk individuals who could benefit from statin therapy and overidentification of very-low-risk individuals who might not experience a net benefit from statin therapy over a 10-year period.

4.8 Heart Failure and Hemodialysis

No recommendation was made with regard to the initiation or continuation of statin therapy in 2 specific groups: 1) individuals with New York Heart Association class II–IV heart failure, and 2) individuals undergoing maintenance hemodialysis. In the 4 RCTs reviewed that specifically addressed statin treatment in these groups, there were individuals with and without heart disease (84–87). Although statin therapy did not reduce ASCVD events in 2 RCTs for each condition (84–87), there was insufficient information on which to base recommendations for or against statin treatment. Future research may identify subgroups of patients with these conditions that may benefit from statin therapy. In individuals with these conditions, the potential for ASCVD risk-reduction benefits, adverse effects, and drug–drug interactions, along with other cautions and contraindications to statin therapy and choice of statin dose, must also be considered by the treating clinician.

RCT data were also used to examine the safety of lipid medications. From the statin RCTs and meta-analyses, patient characteristics and monitoring strategies were identified that should enhance the safe use of high- and moderate-intensity statin therapy. Patient characteristics that may influence statin safety include but are not limited to: multiple or serious comorbidities, including impaired renal or hepatic function; a history of previous statin intolerance or muscle disorders; concomitant use of drugs affecting statin metabolism; a history of hemorrhagic stroke; and age >75 years. Asian ancestry may also influence the initial choice of statin intensity.

This guideline recommends against routine measurement of creatine kinase in individuals receiving statin therapy. This measurement should be reserved for those with muscle symptoms. However, measurement of a baseline creatine kinase may be useful in those at increased risk of adverse muscle events. Such individuals include those with a personal or family history of statin intolerance or muscle disease, clinical presentation, or concomitant drug therapy that might increase the likelihood of myopathy.

Expert recommendations are also provided for managing muscle symptoms while a patient is on statin therapy. These useful management suggestions were derived from other clinical trial data and clinical experience to enhance the safety and tolerability of statin therapy. Consistent with the protocols of the RCTs, patients should be asked at each visit, both before and after initiation of statin therapy, about muscle symptoms such as muscle weakness or fatigue, aching, pain, tenderness, cramps, or stiffness. The recommended approach for management of muscle symptoms is described in Table 8, Recommendation 8.

This guideline recommends that baseline measurement of transaminase (alanine transaminase; ALT) levels should be performed before initiation of statin therapy. This approach was taken in the RCTs reviewed for this report. There is no recommendation to monitor transaminase (ALT) levels because ALT monitoring was performed in the RCTs, and there was no significant difference between placebo groups and statin treatment groups in the rates of ALT elevations. In addition, the U.S. Food and Drug Administration has indicated that if the baseline hepatic transaminases are normal, further hepatic monitoring is not needed. During statin therapy, it is reasonable to measure hepatic function if symptoms suggesting hepatotoxicity arise (e.g., unusual fatigue or weakness, loss of appetite, abdominal pain, dark-colored urine, or yellowing of the skin or sclera).

Decreasing the statin dose may be considered when 2 consecutive values of LDL-C are <40 mg/dL. This recommendation was based on the approach taken in 2 RCTs. However, no data were identified that suggest an excess of adverse events occurred when LDL-C levels were below this level.

Statins modestly increase the excess risk of type 2 diabetes in individuals with risk factors for diabetes. The potential for an ASCVD risk-reduction benefit outweighs the excess risk of diabetes in all but the lowest-risk individuals (Section 4.5). All individuals receiving statins should be counseled on healthy-lifestyle habits. Individuals receiving statin therapy should be evaluated for new-onset diabetes according to the current diabetes screening guidelines (91). Those who develop diabetes during statin therapy should be encouraged to adhere to a heart-healthy dietary pattern, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, and continue statin therapy to reduce their risk of ASCVD events.

Statins are listed as pregnancy category X and should not be used in women of childbearing potential unless these women are using effective contraception and are not nursing.

For individuals taking any dose of statins, it is reasonable to use caution in individuals >75 years of age, as well as in individuals who are taking concomitant medications that alter drug metabolism, taking multiple drugs, or taking drugs for conditions that require complex medication regimens (e.g., those who have undergone solid organ transplantation or are receiving treatment for HIV). A review of the manufacturer’s prescribing information might be useful before initiation of any cholesterol-lowering drug, because RCTs considered defined populations and many patients in everyday practice would not qualify for clinical trials. Thus, clinicians should also consult other sources of safety data, such as pharmacists, drug information centers, and manufacturers’ prescribing information on a regular basis for up-to-date guidance about lipid medications and medication interactions.

Statins used in combination with other cholesterol-lowering drug therapies might require more intensive monitoring. The safety of nonstatin agents was reviewed, and that information is included in Table 9 and the Full Panel Report Supplement. Warnings about the use of cholesterol-lowering agents in pregnancy and lactation also apply to nonstatins, and the manufacturer's prescribing information should be consulted.

6 Managing Statin Therapy: Recommendations

See Table 10 for a summary of recommendations for monitoring, optimizing, and addressing insufficient response to statin therapy.

6.1 Monitoring Statin Therapy

A high level of RCT evidence supports the use of an initial fasting lipid panel (total cholesterol, triglycerides, HDL-C, and calculated LDL-C), followed by a second lipid panel 4 to 12 weeks after initiation of statin therapy, to determine a patient’s adherence. Thereafter, assessments should be performed every 3 to 12 months as clinically indicated. Adherence to both medication and lifestyle regimens are required for ASCVD risk reduction. After statin therapy has been initiated, some individuals experience unacceptable adverse effects when taking the recommended intensity of statin therapy. Once the severity and association of adverse effects with statin therapy has been established, and once factors potentially contributing to statin intolerance are resolved, the patient should be given lower doses of the same statin or an alternative appropriate statin, until a statin and dose that have no adverse effects have been identified (Table 8, Recommendation 8).

See Figure 5 for a flow diagram on monitoring statin response for the initiation of nonstatin therapy.

*Fasting lipid panel preferred. In a nonfasting individual, a non–HDL-C level ≥220 mg/dL may indicate genetic hypercholesterolemia that requires further evaluation or a secondary etiology. If nonfasting triglycerides are ≥500 mg/dL, a fasting lipid panel is required.

†In those already on a statin, in whom baseline LDL-C is unknown, an LDL-C <100 mg/dL was observed in most individuals receiving high-intensity statin therapy in RCTs.

6.2 Optimizing Statin Therapy

Although high-intensity statin therapy reduces ASCVD events more than moderate-intensity statin therapy, lower-intensity statin therapy has also been shown to reduce ASCVD events, although to a lesser degree. Therefore, individuals who merit guideline-recommended statin therapy should be treated with the maximum-appropriate intensity of a statin that does not cause adverse effects.

6.3 Insufficient Response to Statin Therapy

6.3.1 Testing

The evidence is less clear with regard to the most appropriate tests for determining whether an anticipated therapeutic response to statin therapy has occurred on the maximally tolerated dose. RCT evidence to support the use of specific LDL-C or non–HDL-C targets was not identified. The focus is on the intensity of the statin therapy, but as an aid to monitoring response to therapy and adherence, it is reasonable to use the following as indicators of anticipated therapeutic response to statin therapy:

• High-intensity statin therapy generally results in an average LDL-C reduction of ≥50% from the untreated baseline.

• Moderate-intensity statin therapy generally results in an average LDL-C reduction of 30% to <50% from the untreated baseline.

• LDL-C levels and percent reduction are to be used only to assess response to therapy and adherence. They are not to be used as performance standards.

In those already on a statin, in whom the baseline LDL-C is unknown, an LDL-C <100 mg/dL was observed in most individuals receiving high-intensity statin therapy in RCTs.

However, there are many limitations of using LDL-C <100 mg/dL as a fixed target. If a moderate- or low-intensity statin results in an LDL-C level <100 mg/dL in a patient with ASCVD, the evidence suggests that a high-intensity statin, if tolerated, provides a greater reduction in ASCVD events. Conversely, in those with LDL-C levels slightly >100 mg/dL on a high-intensity statin, some options such as niacin might require down-titration of the statin intensity in an effort to improve safety. This would result in a suboptimal intensity of evidence-based statin therapy. Additional limitations to using LDL-C treatment targets are discussed in the Full Panel Report Supplement.

No evidence was found that titration or combination-drug therapy to achieve specific LDL-C or non–HDL-C levels or percent reductions improved ASCVD outcomes. Therefore, this guideline does not recommend their use as performance measures.

The percent LDL-C reduction may not only indicate adherence, but also may reflect biological variability in the response to statin therapy. This acknowledges that some individuals may have less than an average response. Attention to adherence of statin and lifestyle therapy and evaluation and treatment of secondary causes (Table 6) that might elevate LDL-C, may address less-than-anticipated responses to a specific statin dosage. Whether the dose of statin therapy should be increased on the basis of a less-than-anticipated average response should be left to clinical judgment.

6.3.2 Nonstatins Added to Statins or in Statin-Intolerant Individuals

Adherence to lifestyle changes and to statin therapy should be reemphasized before the addition of a nonstatin drug is considered (Figure 5). RCTs evaluating the ASCVD event reductions from nonstatins used as monotherapy were reviewed, as were RCTs evaluating the additional reduction in ASCVD events from nonstatin therapy added to statin therapy. The Expert Panel could find no data supporting the routine use of nonstatin drugs combined with statin therapy to further reduce ASCVD events. In addition, no RCTs that assessed ASCVD outcomes in statin-intolerant patients were found.

Clinicians treating high-risk patients who have a less-than-anticipated response to statins, who are unable to tolerate a less-than-recommended intensity of a statin, or who are completely statin intolerant, may consider the addition of a nonstatin cholesterol-lowering therapy. High-risk individuals include those with ASCVD, those with LDL-C ≥190 mg/dL, and those with diabetes 40–75 years of age. In this situation, this guideline recommends clinicians preferentially prescribe drugs that have been shown in RCTs to provide ASCVD risk-reduction benefits that outweigh the potential for adverse effects and drug–drug interactions, and consider patient preferences.

7 Selected Clinical and Population Subgroups

7.1 Sex and Racial and Ethnic Subgroups

Because the RCT evidence shows that the absolute benefit of statin treatment is proportional to baseline ASCVD risk, treatment decisions for women and racial and ethnic subgroups should be based on the level of ASCVD risk. This conclusion is a departure from previous approaches that focused on LDL-C levels to guide treatment decisions. Statin treatment based on estimated 10-year ASCVD risk avoids the overtreatment of lower-risk groups, such as younger, non-Hispanic white women who, despite moderate elevations in LDL-C, are typically not at significantly increased risk for ASCVD in the next 10 years in the absence of substantial risk factor burden. However, ignoring the increased ASCVD risk in African American women and men might result in the undertreatment of some individuals who are at significantly higher ASCVD risk at the same LDL-C level. Thus, this guideline recommends statin therapy for individuals in whom it is most likely to provide ASCVD risk reduction on the basis of the estimated 10-year risk of ASCVD.

7.2 Individuals >75 Years of Age

Fewer people >75 years of age were enrolled in the statin RCTs reviewed. RCT evidence does support the continuation of statins beyond 75 years of age in persons who are already taking and tolerating these drugs. A larger amount of data supports the use of moderate-intensity statin therapy for secondary prevention in individuals with clinical ASCVD who are >75 years of age. However, the limited information available did not clearly support initiation of high-intensity statin therapy for secondary prevention in individuals >75 years of age.

Few data were available to indicate an ASCVD event reduction benefit in primary prevention among individuals >75 years of age who do not have clinical ASCVD. Therefore, initiation of statins for primary prevention of ASCVD in individuals >75 years of age requires consideration of additional factors, including increasing comorbidities, safety considerations, and priorities of care. The Pooled Cohort Equations can also provide information on expected 10-year ASCVD risk for those 76 to 79 years of age that may inform the treatment decision. These factors may influence decisions about cholesterol-lowering drug therapy, especially in the primary-prevention setting. Accordingly, a discussion of the potential ASCVD risk-reduction benefits, risk of adverse effects, drug–drug interactions, and consideration of patient preferences should precede the initiation of statin therapy for primary prevention in older individuals.

8 Limitations

The evidence-based recommendations in this guideline focus on patient groups who are well represented in RCTs and/or are highly likely to have high-risk genetic conditions, so the recommendations are designed to inform rather than replace clinical judgment. However, there are other patient groups for which a robust evidence base is lacking but that may nevertheless include some persons for whom statin treatment should be considered (after taking patient preferences into account) on the basis of the potential for ASCVD benefits to exceed the risk of adverse events and drug–drug interactions. Clinician judgment is especially important for several patient groups for which the RCT evidence is insufficient for guiding clinical recommendations. These patient groups include younger adults (<40 years of age) who have a low estimated 10-year ASCVD risk but a high lifetime ASCVD risk based on single strong factors or multiple risk factors. Other groups include those with serious comorbidities and increased ASCVD risk (e.g., individuals with HIV or rheumatologic or inflammatory diseases, or who have undergone a solid organ transplantation). This guideline encourages clinicians to use clinical judgment in these situations, weighing potential benefits, adverse effects, drug–drug interactions, and consider patient preferences.

Previous guidelines have taken less rigorous approaches to identifying the evidence to support their recommendations. In contrast, to minimize various sources of bias, the present recommendations are based on data available from RCTs and systematic reviews and meta-analyses of RCTs that were graded as fair to good quality by an independent contractor and were reviewed by the Expert Panel, with the assistance of an independent methodologist. To avoid biases, evidence from post-hoc analyses of included RCTs, from poor-quality RCTs, and from observational studies was not considered. This approach resulted in a comprehensive set of evidence-based clinical recommendations for the treatment of blood cholesterol to reduce ASCVD risk.

9 Evidence Gaps and Future Research Needs

After a systematic review of the literature, several research priorities are suggested that address existing evidence gaps and offer the greatest potential to inform and influence clinical practice and reduce ASCVD morbidity and mortality. High-priority research areas are:

1. Outcomes of RCTs to evaluate statins for the primary prevention of ASCVD in adults >75 years of age.

10 Conclusions

These recommendations arose from careful consideration of an extensive body of higher-quality evidence derived from RCTs and systematic reviews and meta-analyses of RCTs. Rather than LDL-C or non–HDL-C targets, this guideline used the intensity of statin therapy as the goal of treatment. Through a rigorous process, 4 groups of individuals were identified for whom an extensive body of RCT evidence demonstrated a reduction in ASCVD events with a good margin of safety from moderate- or high-intensity statin therapy:

Four Statin Benefit Groups:

1. Individuals with clinical ASCVD

2. Individuals with primary elevations of LDL-C ≥190 mg/dL

3. Individuals 40 to 75 years of age with diabetes and LDL-C 70 to 189 mg/dL without clinical ASCVD

4. Individuals without clinical ASCVD or diabetes who are 40 to 75 years of age and have LDL-C 70 to 189 mg/dL and an estimated 10-year ASCVD risk of ≥7.5%. This requires a clinician-patient discussion.

Individuals in the last group can be identified by using the Pooled Cohort Equations for ASCVD risk prediction developed by the Risk Assessment Work Group. Lifestyle counseling should occur at the initial and follow-up visits as the foundation for statin therapy and may improve the overall risk factor profile.

Most importantly, our focus is on those individuals most likely to benefit from evidence-based statin therapy to reduce ASCVD risk. Implementation of these ASCVD risk-reduction guidelines will help to substantially address the large burden of fatal and nonfatal ASCVD in the United States. We realize that these guidelines represent a change from previous guidelines, but clinicians have become accustomed to change when that change is consistent with the current evidence. Continued accumulation of quality trial data will inform future cholesterol treatment guidelines.

Northwestern University Feinberg School of Medicine—Senior Associate Dean; Chair and Professor of Preventive Medicine; Professor of Medicine (Cardiology)

2008–2012:None

2008–2012:None

2008–2012:None

2008–2012:None

2008–2012:None

2013:None

2013:None

2013:None

2013:None

2013:None

Patrick McBride

University of Wisconsin School of Medicine and Public Health—Professor of Medicine and Family Medicine

2008–2012:None

2008–2012:None

2008–2012:None

2008–2012:None

2008–2012:None

2013:None

2013:None

2013:None

2013:None

2013:None

J. Sanford Schwartz

University of Pennsylvania School of Medicine— Leon Hess Professor of Internal Medicine, Health Management and Economics

2008–2012:

• Abbott

• Allergan

• Amgen

• Daiichi-Sankyo

• Genentech

• Johnson & Johnson

• Merck

• Pfizer

• Shire Pharmaceuticals

2008–2012:None

2008–2012:None

2008–2012:

• Pfizer

2008–2012:None

2013:

• Abbott

• Allergan

• Amgen

• Daiichi-Sankyo

• Genentech

• Johnson & Johnson

• Merck

• Pfizer

• Shire Pharmaceuticals

2013:None

2013:None

2013:

• Pfizer

2013:None

Susan T. Shero Ex-Officio

NHLBI—Public Health Advisor

2008–2012:None

2008–2012:None

2008–2012:None

2008–2012:None

2008–2012:None

2013:None

2013:None

2013:None

2013:None

2013:None

Sidney C. Smith, Jr

University of North Carolina—Professor of Medicine; Center for Cardiovascular Science and Medicine—Director

2008–2012:None

2008–2012:None

2008–2012:None

2008–2012:None

2008–2012:None

2013:None

2013:None

2013:None

2013:None

2013:None

Karol Watson

University of California, Los Angeles School of Medicine—Co-Director

2008–2012:

• Abbott

• AstraZeneca

• Genzyme

• GlaxoSmithKline

• Kos

• Medtronic

• Merck

• Novartis

• Pfizer

2008–2012:None

2008–2012:None

2008–2012:

• Merck

2008–2012:None

2013:None

2013:None

2013:None

2013:

• Merck

2013:None

Peter W.F. Wilson

Atlanta VA Medical Center and Emory University School of Medicine—Professor of Medicine

2008–2012:

• Merck

• XZK

2008–2012:None

2008–2012:None

2008–2012:

• Merck

• Liposcience

2008–2012:None

2013:None

2013:None

2013:None

2013:

• Merck

2013:None

This table reflects the relevant healthcare-related relationships of authors with industry and other entities provided by the panels during the document development process (2008–2012). Both compensated and uncompensated relationships are reported. These relationships were reviewed and updated in conjunction with all meetings and conference calls of the Expert Panel during the document development process. Authors with relevant relationships during the document development process recused themselves from voting on recommendations relevant to their relationships. In the spirit of full transparency, the ACC and AHA asked Expert Panel members to provide updates and approve the final version of this table, which includes current relevant relationships (2013).

A person is deemed to have a significant interest in a business if the interest represents ownership of ≥5% of the voting stock or share of the business entity, or ownership of ≥$10,000 of the fair market value of the business entity; or if funds received by the person from the business entity exceed 5% of the person’s gross income for the previous year. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted.

ACC indicates American College of Cardiology; AHA, American Heart Association; NHLBI, National Heart, Lung, and Blood Institute; and USDA, U.S. Department of Agriculture.

ACC indicates American College of Cardiology; AHA, American Heart Association; NLA, National Lipid Association; and VA, Veterans Affairs.

Appendix 3 Abbreviations

ALT = alanine transaminase

ASCVD = atherosclerotic cardiovascular disease

CHD = coronary heart disease

COR = Class of Recommendation

CQ = critical question

HDL-C = high-density lipoprotein cholesterol

LDL-C = low-density lipoprotein cholesterol

LOE = Level of Evidence

MI = myocardial infarction

NHLBI = National Heart, Lung, and Blood Institute

RCT = randomized controlled trial

RWI = relationships with industry and other entities

Appendix 4 Evidence Statements

ES No.

Evidence Statement

Level of Evidence

Recommendation(s)/Section

References

1

Data are not available regarding treatment or titration to a specific LDL-C goal in adults with CHD/CVD. The Expert Panel found insufficient evidence to support setting LDL-C goals in CHD/CVD patients.

In adults with CHD/CVD who do not have Class II–IV heart failure, fixed high-intensity statin (atorvastatin 80 mg) or statin-niacin treatment that achieved a mean LDL-C 72–79 mg/dL reduced the RR for CHD/CVD events compared with placebo with a mean LDL-C 112–135 mg/dL. In these trials, the mean LDL-C levels were reduced by 45–57 mg/dL or by 45% (HATS [121]) to 53% (SPARCL [107]).

In adults with CHD/CVD and diabetes, fixed high-intensity statin treatment (atorvastatin 80 mg) that achieved a mean LDL-C of 57–77 mg/dL reduced the RR for CHD/CVD events more than fixed lower-intensity statin treatment that achieved a mean LDL-C of 81–99 mg/dL. In these trials, the mean LDL-C levels achieved differed by 22–24 mg/dL, or 22%–30%, between the 2 groups.

In adults ≥65 years of age with CHD/CVD, fixed high-intensity statin treatment (atorvastatin 80 mg) that achieved a mean LDL-C of 72 mg/dL reduced CHD/CVD events more than fixed lower-intensity statin treatment that achieved a mean LDL-C of 97 mg/dL. In this trial, the mean LDL-C levels achieved differed by 25 mg/dL, or 26%, between the 2 groups. In adults ≥65 years of age with a history of stroke or TIA, higher fixed-dose statin treatment that achieved a mean LDL-C of 72 mg/dL reduced CHD events more than placebo, with a mean LDL-C of 129 mg/dL. In this trial, the mean LDL-C level was reduced by 61 mg/dL, or 46%, from baseline in those ≥65 years of age.

In adults with and without CVD, in trials comparing more intensive to less intensive statin therapy or statin therapy with placebo/control, the relative CVD risk reduction was similar for those <65 years, 65 to ≤75, or >75 years of age. There is less information to estimate the magnitude of benefit in those under age 45 or over age 75 years, because fewer participants in these age groups were enrolled in clinical trials. More intensive statin therapy did not appear to reduce CVD risk, compared with less intensive statin therapy, in those with ASCVD and age >75 years. Statin therapy, compared with control (most RCTs evaluated moderate-intensity statin therapy), had a similar magnitude of RR reduction in those >75 as in those ≤75 years of age with and without ASCVD.Statin therapy vs. control trials = atorvastatin (A) 10–20 mg, fluvastatin (F) 80 mg, lovastatin (L) 40–80 mg, pravastatin (P) 40 mg, rosuvastatin (R)10–20 mg, simvastatin (S) 40 mg.See Table 4 for the Expert Panel’s definitions for high-, moderate-, and low-intensity statin therapy.The Panel uses moderate intensity to refer to statin drugs and doses that lower LDL-C by 30% to approximately 50%.This dose refers to atorvastatin 10 mg, fluvastatin 80 mg, lovastatin 40 mg, pravastatin 40 mg, rosuvastatin 10 mg, and simvastatin 40 mg.

In adults with CHD (including acute coronary syndromes, or a history of MI, stable or unstable angina, coronary revascularization), statin therapy reduced the RR for CVD events by approximately 21% per 1-mmol/L (38.7-mg/dL) LDL-C reduction. This relationship was similar for more intensive compared with less intensive statin therapy and for statin therapy compared with placebo/control.

In adults with CVD other than CHD (including stroke, TIA presumed to be of atherosclerotic origin, or peripheral arterial disease or revascularization), statin therapy reduced the RR for CVD events by approximately 19% per 1-mmol/L (38.7-mg/dL) LDL-C reduction. This relationship was similar for more intensive compared with less intensive statin therapy and for statin therapy compared with placebo/control.

In adults with and without CVD, in trials comparing more* intensive with less intensive statin therapy, or statin therapy with placebo/control, there were no clinically important differences in the CVD risk reduction between the subgroups listed below:

In more vs. less statin and statin vs. control trials combined, each 1-mmol/L (38.7-mg/dL) reduction in LDL-C resulted in approximately 22% reductions in CVD risk across baseline LDL-C levels [<2 mmol/L (77 mg/dL), ≥2 to <2.5 mmol/L (97 mg/dL), ≥2.5 to <3.0 mmol/L (116 mg/dL), ≥3.0 to <3.5 mmol/L (135 mg/dL), and ≥3.5 mmol/L, either untreated or on statin therapy]. In the statin vs. placebo/control trials, those with LDL-C <2 mmol/L may have experienced less benefit than those with higher LDL-C level.

In adults, statins reduce the RR for CVD, CHD, and fatal CHD similarly in those with or without hypertension. This benefit applies across all levels of baseline systolic and diastolic blood pressure and in those with treated hypertension.

In adults with and without CVD who received more intensive compared with less intensive statin therapy, or statin therapy compared with placebo/control, the RR for first stroke was reduced by approximately 16% per 1-mmol/L (38.7-mg/dL) LDL-C reduction, primarily because of an approximately 21% reduction in the RR for ischemic stroke.

In adults with CHD or acute coronary syndromes who received more intensive compared with less intensive statin therapy, the RR for coronary revascularization was reduced by approximately 34% per 1-mmol/L (38.7-mg/dL) LDL-C reduction.

In adults with and without CVD who received statin therapy compared with placebo/control, the RR for coronary revascularization was reduced by approximately 24% per 1-mmol/L (38.7-mg/dL) LDL-C reduction.

In adults with and without CVD who received statin therapy, there was no variation in the relative reduction of CVD risk among the trials after adjustment for LDL-C reduction. Thus, LDL-C reduction appeared to account for the reduction in CVD risk.

In adults with diabetes (some of whom had CHD), statin therapy reduced the RR for CVD events by approximately 20% per 1-mmol/L (38.7-mg/dL) LDL-C reduction. This 1-mmol (20%) risk-reduction relationship was similar for more intensive compared with less intensive statin therapy and for statin therapy compared with placebo/control.

In adults with diabetes, statin therapy reduced the RR for CVD by a similar magnitude for subgroups of diabetic men and women, <65 and ≥65 years of age; treated hypertension; body mass index <25, >25 to <30, and ≥30; systolic blood pressure <160 and ≥160 mm Hg; diastolic blood pressure <90 and ≥90 mm Hg; current smokers and nonsmokers; estimated GFR <60, ≥60 to <90, and ≥90 mL/min/1.73 m2; and predicted annual risk for CVD <4.5%, >4.5% to <8.0%, and ≥8.0%. Whereas RRRs are similar across these subgroups, absolute risk reductions may differ for various subgroups.

In adults 40 to 75 years of age with diabetes and ≥1 risk factor, fixed moderate-dose statin therapy that achieved a mean LDL-C of 72 mg/dL reduced the RR for CVD by 37% (in this trial, LDL-C was reduced by 46 mg/dL or 39%).

In men and postmenopausal women 40 to 73 years of age without CHD/CVD, the majority of whom did not have diabetes and had baseline LDL-C levels <190 mg/dL, fixed low- to moderate-dose statin therapy that achieved a mean LDL-C of 115–127 mg/dL reduced the RR for CVD by 24%–25%, compared with placebo, with mean LDL-C levels of 153–156 mg/dL. (In these trials, LDL-C was reduced by 29–35 mg/dL and 19%–25% from baseline with a low- to moderate-dose statin.)

In men ≥50 years and women ≥60 years of age without CHD/CVD with LDL <130 mg/dL and hs-CRP ≥2 mg/L, fixed intensive-dose statin that achieved a mean LDL-C of 53 mg/dL reduced the RR for CVD events by 44% compared with placebo, which had a mean LDL-C 110 mg/dL. In this trial, LDL-C was reduced by 53 mg/dL, or 49%.

In adults without CVD (some of whom had diabetes) who received more intensive or less intensive statin therapy, or statin therapy compared with placebo/control, the RR for CVD events was reduced by approximately 25% per 1-mmol/L LDL-C reduction. This was similar to the CVD RRR observed in those with CHD or CVD.

Statin therapy, with a range of LDL-C lowering, reduces all-cause mortality, compared with placebo, in primary-prevention clinical trials of adults who were in general ≥40 years of age and had at least 1 risk factor, and with a wide range of baseline LDL-C levels.

In adults without CVD (some of whom had diabetes) overall, who received statin therapy compared with placebo/control, the RR for CVD events was reduced by approximately 25% per 1-mmol/L LDL-C reduction. This was similar to the CVD RRR observed in those with CHD or CVD.

Statin therapy, with a range of LDL-C lowering, reduces all-cause mortality by about 10%, compared with placebo, in primary-prevention clinical trials of adults who were ≥40 years of age and in general who had at least 1 risk factor, and with a wide range of baseline LDL-C levels.

In adults with and without CVD, intensive- and moderate-dose statins do not increase the risk for death from noncardiovascular causes, regardless of baseline LDL-C. Statins do not increase (or decrease) the risk for incident cancer overall or cancer of any type, or the risk for cancer death.

• Assessed for adverse effects by history and laboratory measurements at every visit or every other visit.

• Able to reduce the statin dose for adverse events so that atorvastatin 80 mg could be reduced to 40 mg (IDEAL [47], PROVE-IT [48]) or pravastatin 40 mg could be reduced to 20 mg (PROVE-IT [48]) or simvastatin reduced by 10 mg/d (HATS [121]).

• Able to reduce the statin dose if LDL-C decreased to <39 mg/dL (1.0 mmol/L) (per investigator discretion in IDEAL [47]) or reduce the statin dose if total cholesterol was <100 mg/dL on 2 successive visits (AFCAPS [17]) or reduce by 10 mg simvastatin per day if LDL-C was <40 mg/d (HATS [121]), although they continued on study drug no matter how low the cholesterol in CARDS (75).

• Allowed to have their statin doses uptitrated or switched to more potent statin to further reduce

In adults with and without CVD who received more intensive compared with less intensive statin therapy, or statin therapy compared with placebo/control, overall the RR for first hemorrhagic stroke was not increased. Hemorrhagic stroke comprised 11% of total strokes in the more intensive/statin group, compared with 8% in the less intensive/control groups.

Low- to moderate-dose statin therapy has similar rates of elevated hepatic transaminase levels as placebo/no statin treatment. In general, clinical trials tend to underestimate those likely to have side effects, often related to selection procedures.

In adults with CHD, CK elevation ≥3 times ULN occurs infrequently and at a similar rate in those treated with intensive- or moderate-dose statin therapy (0.02% [moderate-dose statin] to 0.1% [higher-dose statin]) over a 1- to 5-year treatment period (RR 2.63, 95% CI 0.88–7.85).

In adults 45 years of age and older with established CVD and low HDL-C (<40 mg/dL in men or <50 mg/dL in women), elevated triglycerides (150–400 mg/dL), and LDL-C <180 mg/dL off statin, in whom the dose of simvastatin was adjusted, or ezetimibe was added, to maintain LDL-C in a range of 40–80 mg/dL, extended-release niacin 1,500–2,000 mg/day plus simvastatin (9.5% also on ezetimibe 10 mg) compared with placebo (with 50 mg immediate-release niacin) plus simvastatin (21.5% also on ezetimibe 10 mg:

• Improved the lipid profile without a further decrease in CVD events. Specifically, it lowered LDL-C levels an additional 6%, increased HDL-C by an additional 14%, reduced triglycerides by an additional 23%, lowered apolipoprotein B by an additional 10%, and reduced lipoprotein(a) by an additional 19%.

• There were similar rates of CVD events in subgroups by age, sex, or diabetes, metabolic syndrome, or previous myocardial infarction status, as well as similar rates of adverse events, including liver function abnormalities, muscle symptoms, and rhabdomyolysis.

• Lipids, LFTs, uric acid, and glucose were monitored during up-titration and every 3–12 months thereafter.

In adults 40–79 years of age with diabetes, CVD, and/or CVD risk factors, with LDL-C 60–180 mg/dL, HDL-C <55 mg/dL in women and black individuals, HDL-C <50 mg/dL for all others, and triglycerides <750 mg/dL on no medication or <400 mg/dL on medication:

In men 40–55 years of age without CHD or CHF and non–HDL-C ≥200 mg/dL, gemfibrozil:

• Reduced LDL-C by 10% and triglycerides by 43%, and increased HDL-C by 10%.

• Reduced the RR for CHD by 37%, compared with placebo.

• Increased skin cancer, increased gastrointestinal surgery, and increased severe upper gastrointestinal symptoms, especially in first year. There was no difference in diarrhea, constipation, nausea, or vomiting. Total mortality was not reported.

In men and women of mean age 58 to 68 years with aortic stenosis, treatment with statin or statin plus ezetimibe for a mean of 2.1–4.4 years resulted in a reduction in LDL-C of 50%–55% (67–73 mg/dL) from a baseline LDL-C of 123–140 mg/dL and did not alter the progression of aortic stenosis as assessed by change in valve area, peak aortic valve jet velocity, peak or mean aortic valve gradient, or need for aortic valve surgery.

Appendix 5 Expanded Discussion of What’s New in the Guideline

Focus on ASCVD Risk Reduction: 4 Statin Benefit Groups

• The 2013 guideline focuses on treatment of blood cholesterol to reduce ASCVD risk. Each Expert Panel was limited in the number of CQs it could choose. When the CQs from the Risk Assessment and Lifestyle Work Groups were combined with the 3 Cholesterol Panel CQs, there were 8 CQs in total that were systematically reviewed. All 3 CQs of the Cholesterol Panel evaluated evidence from RCTs with ASCVD outcomes. CQ1 and CQ2 evaluated the evidence for LDL-C and non–HDL-C goals in secondary and primary prevention. CQ3 was a comprehensive evaluation of the reduction in ASCVD events and safety for each of the cholesterol-lowering drugs available in the United States.

• The systematic review of evidence from the highest-quality RCTs with ASCVD outcomes identified strong evidence to indicate who should get which therapy at what intensity.

• The statin RCTs provided the most extensive evidence for the greatest magnitude of ASCVD event reduction, with the best margin of safety.

• Four statin benefit groups were identified, in which the potential for an ASCVD risk-reduction benefit clearly exceeds the potential for adverse effects in:

1. Individuals with clinical ASCVD

2. Individuals with primary elevations of LDL-C ≥190 mg/dL

3. Individuals 40–75 years of age with diabetes but without clinical ASCVD and LDL-C 70–189 mg/dL

4. Individuals 40–75 years of age without diabetes or clinical ASCVD with LDL-C 70–189 mg/dL and an estimated 10-year ASCVD risk of 7.5% or higher. This requires a clinician-patient discussion.

• Because few trials have been performed with nonstatin cholesterol-lowering drugs in the statin era, and those that have been performed were unable to demonstrate significant additional ASCVD event reductions in the RCT populations studied, there was less evidence to support the use of nonstatin drugs for ASCVD prevention.

• It is difficult to determine how observational data could override the conclusions from the extensive body of evidence from the statin RCTs and the paucity of evidence from nonstatin RCTs. Inherent biases of observational data are well understood and include biases in the decisions on whom to treat and who is adherent to therapy, as well as multiple measurement biases, including verification of statin use, type and dose of statin used, consistency of use over time, and outcome ascertainment. All of these problems are addressed in intent-to-treat analyses of RCTs, which is why the FDA requires well-designed RCTs to determine drug efficacy for ASCVD event reduction and common adverse effects.

• Other approaches to treatment of blood cholesterol have been advocated, including:

A.Treat to target—This strategy has been the most widely used in the past 15 years, but there are 3 problems with this approach. First, current clinical trial data do not indicate what the target should be. Second, we do not know the magnitude of additional ASCVD risk reduction that would be achieved with one target lower than another. Third, this strategy does not take into account potential adverse effects from statin monotherapy or from multidrug therapy that might be needed to achieve a specific goal. Thus, in the absence of these data, this approach is less useful than it appears (Section 3). It is possible that future clinical trials may provide information warranting reconsideration of this strategy.

B.Lowest is best—This approach was not taken because it does not consider the potential adverse effects of multidrug therapy with an unknown magnitude of ASCVD event reduction. Ongoing RCTs of new LDL-C–lowering drugs in the setting of maximal statin therapy may address this question.

C.Treat level of ASCVD risk—A modified version of this approach was taken, which considers both the ASCVD risk-reduction benefits and the adverse effects of statin treatment on the basis of an extensive body of RCT evidence to determine the 4 statin benefit groups. By focusing treatment on the 4 statin benefit groups, the approach is practical and simpler to implement than the past strategies. There are also important exceptions for routine initiation of statin treatment for individuals requiring hemodialysis or with NYHA class II to IV heart failure.

D.Lifetime risk—Treatment strategies based on lifetime ASCVD risk are problematic because of the lack of data on the long-term follow-up of RCTs >15 years, the safety and ASCVD event reduction when statins are used for periods >10 years, and treatment of individuals <40 years of age.

A New Perspective on LDL-C and/or Non–HDL-C Goals

• The difficulty of giving up the treat-to-goal paradigm was deliberated extensively over a 3-year period. Many clinicians use targets such as LDL-C <70 mg/dL and LDL-C <100 mg/dL for secondary and primary ASCVD prevention (non–HDL-C targets are 30 mg/dL higher). However, the RCT evidence clearly shows that ASCVD events are reduced by using the maximum-tolerated statin intensity in those groups shown to benefit. After a comprehensive review, no RCTs were identified that titrated drug therapy to specific LDL-C or non–HDL-C goals to improve ASCVD outcomes. However, one RCT was identified that showed no additional ASCVD event reduction from the addition of nonstatin therapy to further treat non–HDL-C levels once an LDL-C goal was reached. In AIM-HIGH (9), the additional reduction in non–HDL-C levels [as well as additional reductions in Apo B, Lp(a), and triglycerides in addition to HDL-C increases] with niacin therapy DID NOT further reduce ASCVD risk in individuals treated to LDL-C levels of 40–80 mg/dL.

• Use of LDL-C targets may result in under treatment with evidence-based statin therapy or overtreatment with nonstatin drugs that have not been shown to reduce ASCVD events in RCTs (even though the drug may additionally lower LDL-C and/or non–HDL-C). Implications of treating to an LDL-C goal may mean that a suboptimal intensity of statin is used because the goal has been achieved, or that adding a nonstatin therapy to achieve a specific target results in down-titration of the evidence-based intensity of statin for safety reasons. However, when RCT evidence is available that a nonstatin therapy further reduces ASCVD events when added to statin therapy, the nonstatin therapy may be considered.

• Some examples comparing a strategy based on the 4 statin benefit groups to a strategy using LDL-C/non–HDL-C targets:

A.Secondary prevention—Evidence supports high-intensity statin therapy for this group to maximally lower LDL-C. It does not support the use of an LDL-C target. For example, if a secondary-prevention patient achieves an LDL-C of 78 mg/dL on a dose of 80 mg of atorvastatin, he/she is receiving evidence-based therapy. As of yet, there are no data to show that adding nonstatin drug(s) to high-intensity statin therapy will provide incremental ASCVD risk-reduction benefit with an acceptable margin of safety. Indeed, AIM-HIGH (9) demonstrated the futility of adding niacin in individuals with low HDL-C and high triglycerides, and ACCORD (14) demonstrated the futility of adding fenofibrate in persons with diabetes. Although an ACCORD subgroup analysis of those with high triglycerides and low HDL-C levels suggested that fenofibrate may reduce ASCVD events in patients with diabetes, this is hypothesis generating and needs further testing in comparison to the evidence-based use of a high-intensity statin. In addition, not having a goal of <70 mg/dL for LDL-C means that the patient who is adhering to optimal lifestyle management and receiving a high-intensity statin avoids additional, non–evidence-based therapy just because his/her LDL-C is higher than an arbitrary cutpoint. Indeed, the LDL-C goal approach can make this patient unnecessarily feel like a failure.

B.Familial hypercholesterolemia with LDL-C ≥190 mg/dL—In many cases, individuals with familial hypercholesterolemia are unable to achieve an LDL-C goal <100 mg/dL. For example, an individual with familial hypercholesterolemia may achieve an LDL-C of only 120 mg/dL despite use of 3 cholesterol-lowering drugs. Although this patient may have fallen short of the 100-mg/dL goal, he/she has decreased his/her LDL-C by >50% (starting from an untreated LDL-C level of ∼325–400 mg/dL). These patients are not treatment failures, as observational data has shown significant reductions in ASCVD events without achieving specific LDL-C targets. This is an area where observational data supports the recommended approach.

C.Type 2 diabetes—For those 40–75 years of age with risk factors, the potential benefits of LDL-C lowering with a high-intensity statin are substantial. Because those with diabetes often have lower LDL-C levels than those without diabetes, “goal”-directed therapy often encourages use of a lower statin dose than is supported by the RCTs, and nonstatin drugs may be added to address low HDL-C or high triglycerides, for which RCT evidence of an ASCVD event reduction is lacking. Giving a maximally tolerated statin intensity should receive primary emphasis because it most accurately reflects the data that statins reduce the relative risk of ASCVD events similarly in individuals with and without diabetes, and in primary and secondary prevention in those with diabetes, along with evidence that high-intensity statins reduce ASCVD events more than moderate-intensity statins.

D.Estimated 10-year ASCVD risk ≥7.5%—Data have shown that statins used for primary prevention have substantial ASCVD risk-reduction benefits across the range of LDL-C levels of 70–189 mg/dL. Moreover, the Cochrane meta-analysis (15), as well as a meta-analysis by the Cholesterol Treatment Trialists (13), confirms that primary prevention with statins reduces total mortality as well as nonfatal ASCVD events.

• RCTs are used to identify those who are unlikely to benefit from initiation of statin therapy despite being at high ASCVD risk, such as those with higher NYHA classes of heart failure or those on hemodialysis.

Global Risk Assessment for Primary Prevention

• Use of the new Pooled Cohort Equations is recommended to estimate 10-year ASCVD risk in both white and black men and women who do not have clinical ASCVD.

• By more accurately identifying higher-risk individuals for statin therapy, the guideline focuses statin therapy on those most likely to benefit.

• It also indicates, on the basis of RCT data, those high-risk groups that might not benefit. The Expert Panel emphasizes that the guideline is “patient centered” in primary prevention. It is recommended that the potential for an ASCVD risk-reduction benefits, adverse effects, and drug–drug interactions, along with patient preferences, must be considered before statins are initiated for the primary prevention of ASCVD. Other factors such as LDL-C ≥160 mg/dL may also be considered. This gives clinicians and patients the opportunity for input into treatment decisions rather than a simplistic “one-treatment-fits-all” approach to drug therapy.

• These guidelines are not a replacement for clinical judgment; they are meant to guide and inform decision making.

• Some worry that a person 70 years of age without other risk factors will receive statin treatment on the basis of age alone. The estimated 10-year risk is still ≥7.5%, a risk threshold for which a reduction in ASCVD risk events has been demonstrated in RCTs. Most ASCVD events occur after age 70 years, giving individuals ≥70 years of age the greatest potential for absolute risk reduction.

• Some have proposed using selected inclusion criteria from RCTs to determine the threshold for statin initiation. However, the Cholesterol Treatment Trialists individual-level meta-analysis showed that statin therapy reduces ASCVD events regardless of categorical risk factors in both primary and secondary prevention. Therefore, the rationale for using fixed cutpoints to determine whether statin therapy should be initiated is refuted by a consideration of the total body of evidence from RCTs.

• In addition, a trial-based strategy identifies those at increased ASCVD risk less accurately than does a strategy based on an assessment of global ASCVD risk. This selective use of inclusion criteria excludes well-established risk factors, such as smoking and advancing age (the strongest risk factor because it represents cumulative risk factor exposure).

• The poor discrimination of RCT inclusion criteria for identifying those at increased 10-year ASCVD risk is shown by a calculation performed by the Risk Assessment Work Group using nationally representative data from NHANES. Use of the RCT inclusion criteria (from RCTs that found a reduction in ASCVD events to guide initiation of statin therapy) would result in the treatment of 16% of individuals with <2.5% estimated 10-year ASCVD risk and 45% of those with 2.5% to <5% estimated 10-year ASCVD risk (many would say inappropriately), whereas 38% of those with ≥7.5% 10-year ASCVD risk would not have been identified as candidates for statin therapy.

Safety

• RCTs are used to identify important safety considerations in individuals receiving treatment of blood cholesterol to reduce ASCVD risk and to determine statin adverse effects to facilitate understanding of the net benefit from statin therapy.

• Safety issues that are uncommon or unlikely to be seen in the populations studied in RCTs require more than analyses of single RCTs. This limitation was overcome, in part, by considering high-quality systematic reviews and meta-analyses of statin RCTs.

• This guideline emphasizes the importance of using additional sources of information on safety, including FDA reports, manufacturers’ prescribing information, and pharmacists, to aid in the safe use of cholesterol-lowering drug therapy.

Role of Biomarkers and Noninvasive Tests

• There is a concern about other factors that may indicate elevated ASCVD risk but were not included in the Pooled Cohort Equations for predicting 10-year ASCVD risk.

• The Risk Assessment Work Group has performed an updated systematic review of nontraditional risk factors, such as CAC, and has included recommendations to consider their use to the extent that the evidence allows.

• In selected individuals who are not in 1 of the 4 statin benefit groups, and for whom a decision to initiate statin therapy is otherwise unclear, additional factors may be considered to inform treatment decision making.

• These factors include primary LDL-C ≥160 mg/dL or other evidence of genetic hyperlipidemias; family history of premature ASCVD with onset <55 years of age in a first-degree male relative or <65 years of age in a first-degree female relative; high-sensitivity C-reactive protein ≥2 mg/L; CAC score ≥300 Agatston units or ≥75th percentile for age, sex, and ethnicity; ankle-brachial index <0.9; and elevated lifetime risk of ASCVD. Additional factors may be identified in the future.

Future Updates to the Blood Cholesterol Guideline

• This guideline focuses on treatments proven to reduce ASCVD events. It is not and was never intended to be a comprehensive approach to lipid management.

• Using RCT evidence assessed for quality provides a strong foundation for treatment of blood cholesterol to reduce ASCVD risk that can be used now. There are many clinical questions for which there is an absence of RCT data available to develop high-quality, evidence-based recommendations. For these questions, expert opinion may be helpful to clinicians and could be developed in the next iteration of the guideline.

Footnotes

Endorsed by the American Academy of Physician Assistants, American Association of Cardiovascular and Pulmonary Rehabilitation, American Pharmacists Association, American Society for Preventive Cardiology, Association of Black Cardiologists, Preventive Cardiovascular Nurses Association, and WomenHeart: The National Coalition for Women With Heart Disease

☆ The Journal of the American College of Cardiology is published on behalf of the American College of Cardiology Foundation by Elsevier Inc.; Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDervis License, which permits use, distribution, and reproduction in any medium, provided that the Contribution is properly cited, the use is noncommercial, and no modifications or adaptations are made.

This document was approved by the American College of Cardiology Board of Trustees and the American Heart Association Science Advisory and Coordinating Committee in November 2013. The Academy of Nutrition and Dietetics affirms the value of this guideline.

Copies: This document is available on the World Wide Web sites of the American College of Cardiology (http://www.cardiosource.org) and the American Heart Association (my.americanheart.org). For copies of this document, please contact the Elsevier Inc. Reprint Department, fax (212) 462-1935, e-mail reprints{at}elsevier.com.

National Cholesterol Education Program (U.S.) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)

(2002) Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adults Treatment Panel III) Final report. Circulation106:3143–3421.

(1998) Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA279:1615–1622.

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults

(2001) Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA285:2486–2497.

(2002) Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes: results of the assessment of diabetes control and evaluation of the efficacy of niaspan trial. Arch Intern Med162:1568–1576.

(2006) Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non–insulin-dependent diabetes mellitus (ASPEN). Diabetes Care29:1478–1485.

(2010) Relation of different measures of low-density lipoprotein cholesterol to risk of coronary artery disease and death in a meta-regression analysis of large-scale trials of statin therapy. Am J Cardiol105:1289–1296.

(2008) Usefulness of pravastatin in primary prevention of cardiovascular events in women: analysis of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA study). Circulation117:494–502.

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